Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are gut peptides secreted from the small intestine in response to dietary lipids, and each reduces food intake. CCK acts on local receptors on duodenal sensory nerves and sends a message to the hindbrain via the vagus nerve, whereas apo AIV reduces meal size via unknown pathways to the brain. Recently, we found that intraperitoneal (ip) administration of combined apo AIV and CCK additively reduces meal size and this interaction activates the CCK1 receptor (CCK1R). We also found that subdiaphragmatic vagal dafferentiation (SDA) attenuates the inhibition of food intake induced by perpheral CCK. In contrast, ip apo AIV still decreases food intake following SDA, and the effect is enhanced. Our preliminary data indicate that apo AIV knockout mice are more sensitive to ip CCK than WT controls and have increased gene expression of the CCK1R,in the NTS; also, CCK-deficient mice do not reduce their food intake in response to ip apo AIV. These findings suggest that: 1) interaction of peripheral CCK and apo AIV normally reduces meal size; 2) peripheral apo AIV requires activity at CCK1R in NTS; 3) ip-injected apo AIV requires CCK in inhibiting food intake; and 4) peripheral apo AIV controls food intake via vagal and non-vagal pathways. The potency of satiation in response to CCK is reduced by maintenance on a high-fat diet (HFD). However, the effect of a HFD on sensitivity to apo AIV is not known. In Specific Aim 1, we will test the hypothesis that the interaction of ip or intracerebroventricular (ivt) apo AIV and ip/ivt CCK reduce meal size via the afferent vagus, possibly within the hindbrain. In Specific Aim 2, we will test the hypothesis that ip or ivt CCK and apo AIV interact to reduce food intake in the hypothalamus. In both Aims, we hypothesize that specific CCK receptors mediate the interaction, and we further hypothesize that the brain melanocortin system is involved. In Specific Aim 3, we will test the hypothesis that administering CCK or apo AIV, ivt but not ip, will restore sensitivity in HFD-induced obese animals and result in an inhibition of food intake. RELEVANCE (See instructions):